Adjuvant therapies and sepsis from multidrug resistant bacteria: a narrative review
1Department of women, child, general and specialistic surgery. University of Campania “L. Vanvitelli”, 80138 Naples, Italy
2Department of Clinical Medicine, Public health, Science of Life and environment. University of L’Aquila, 67100 L’Aquila, Italy
3Pegaso University, 80123 Naples, Italy
Submitted: 07 July 2022 Accepted: 28 October 2022
Online publish date: 16 February 2023
*Corresponding Author(s): Vincenzo Pota E-mail: firstname.lastname@example.org
Sepsis represents one of the major health problem due to the high mortality rate and elevated health care costs. An important role in the genesis and the mechanisms sustaining sepsis has been found in the release of pro-inflammatory mediators. They are able to induce hemodynamic instability, end-organ dysfunction, and coagulation abnormalities. The host immune response involves a first extreme response to infective process that leads to tissue damage, organ failure and endothelial dysfunction. It was recently described the existence of a contrasting process, that is directed to restore homeostasis and it’s related with the release of anti-inflammatory mediators. The treatment of sepsis and septic shock could therefore benefit from the association of source control and antibiotic therapy with the use of drugs and other techniques, that act by modulating the cytokine storm. This approach is referred to an adjuvant therapy. The goal of this narrative review is to examine the various adjuvant therapies in the treatment of sepsis and septic shock.
Blood purification; Vitamin C; Thymosin; IVIg; GM-CSF; Interferon gamma
Vincenzo Pota,Francesco Coppolino,Antonella Paladini,Francesca Maglio,Maria T. Sacco,Vittoria Iorio,Giuseppe S. Mangoni,Fabiana Broccoli,Maurizio Del Prete,Pasquale Sansone,Maria B. Passavanti,Alfonso Barbarisi,Caterina Aurilio,Maria C. Pace. Adjuvant therapies and sepsis from multidrug resistant bacteria: a narrative review. Signa Vitae. 2023.doi:10.22514/sv.2023.011.
 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016; 315: 801–810.
 Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016; 315: 775–787.
 Delano MJ, Ward PA. The immune system’s role in sepsis progression, resolution, and long-term outcome. Immunological Reviews. 2016; 274: 330–353.
 Aurilio C, Corcione A, Fraganza F, Sansone P, Paladini A, Passavanti MB, et al. Sedation and analgesia in critically ill patients with COVID-19: a cohort retrospective study. Signa Vitae. 2021; 17; 52–57.
 Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011; 306: 2594.
 Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (GenIMS) study. Archives of Internal Medicine. 2007; 167: 1655–1663.
 Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive Care Medicine. 2018; 44: 925–928.
 Ronco C, Tetta C, Mariano F, Wratten ML, Bonello M, Bordoni V, et al. Interpreting the mechanisms of continuous renal replacement therapy in sepsis: the peak concentration hypothesis. Artificial Organs. 2003; 27: 792–801.
 Honoré PM, Matson JR. Extracorporeal removal for sepsis: acting at the tissue level–the beginning of a new era for this treatment modality in septic shock. Critical Care Medicine. 2004; 32: 896–897.
 Di Carlo JV, Alexander SR. Hemofiltration for cytokine-driven illnesses: the mediator delivery hypothesis. The International Journal of Artificial Organs. 2005; 28: 777–786.
 Peng Z, Singbartl K, Simon P, Rimmelé T, Bishop J, Clermont G, et al. Blood purification in sepsis: a new paradigm. Contributions to Nephrology. 2010; 165: 322–328.
 Rimmelé T, Kellum JA. Clinical review: blood purification for sepsis. Critical Care. 2011; 15: 205.
 Joannes-Boyau O, Honoré PM, Perez P, Bagshaw SM, Grand H, Canivet J, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Medicine. 2013; 39: 1535–1546.
 Quenot JP, Binquet C, Vinsonneau C, Barbar SD, Vinault S, Deckert V, et al. Very high volume hemofiltration with the Cascade system in septic shock patients. Intensive Care Medicine. 2015; 41: 2111–2120.
 Morgera S, Haase M, Kuss T, Vargas-Hein O, Zuckermann-Becker H, Melzer C, et al. Pilot study on the effects of high cutoff hemofiltration on the need for norepinephrine in septic patients with acute renal failure. Critical Care Medicine. 2006; 34: 2099–2104.
 Villa G, Chelazzi C, Morettini E, Zamidei L, Valente S, Caldini AL, et al. Organ dysfunction during continuous veno-venous high cut-off hemodialysis in patients with septic acute kidney injury: a prospective observational study. PLoS One. 2017; 12: e0172039.
 Chelazzi C, Villa G, D’Alfonso MG, Mancinelli P, Consales G, Berardi M, et al. Hemodialysis with high cut-off hemodialyzers in patients with multi-drug resistant gram-negative sepsis and acute kidney injury: a retrospective, case-control study. Blood Purification. 2016; 42: 186–193.
 Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Medicine Experimental. 2018; 6: 12.
 Monard C, Rimmelé T, Ronco C. Extracorporeal blood purification therapies for sepsis. Blood Purification. 2019; 47: 2–15.
 Pota V, Passavanti MB, Sansone P, Pace MC, Peluso F, Fiorelli A, et al. Septic shock from descending necrotizing mediastinitis-combined treatment with IgM-enriched immunoglobulin preparation and direct polymyxin B hemoperfusion: a case report. Journal of Medical Case Reports. 2018; 12: 55.
 Cruz DN, Antonelli M, Fumagalli R, Foltran F, Brienza N, Donati A, et al. Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS randomized controlled trial. JAMA. 2009; 301: 2445–2452.
 Payen D. Haemoperfusion with polymyxin B membrane: recent results for an old debate! Anaesthesia Critical Care & Pain Medicine. 2019; 38: 3–4.
 Klein DJ, Foster D, Walker PM, Bagshaw SM, Mekonnen H, Antonelli M. Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. Intensive Care Medicine. 2018; 44: 2205–2212.
 Chang T, Tu YK, Lee CT, Chao A, Huang CH, Wang MJ, et al. Effects of polymyxin B hemoperfusion on mortality in patients with severe sepsis and septic shock: a systemic review, meta-analysis update, and disease severity subgroup meta-analysis. Critical Care Medicine. 2017; 45: e858–e864.
 Ala-Kokko TI, Laurila J, Koskenkari J. A new endotoxin adsorber in septic shock: observational case series. Blood Purification. 2011; 32: 303–309.
 Yaroustovsky M, Abramyan M, Popok Z, Nazarova E, Stupchenko O, Popov D, et al. Preliminary report regarding the use of selective sorbents in complex cardiac surgery patients with extensive sepsis and prolonged intensive care stay. Blood Purification. 2009; 28: 227–233.
 Adamik B, Zielinski S, Smiechowicz J, Kübler A. Endotoxin elimination in patients with septic shock: an observation study. Archivum Immunologiae et Therapiae Experimentalis. 2015; 63: 475–483.
 Lipcsey M, Tenhunen J, Sjölin J, Frithiof R, Bendel S, Flaatten H, et al. Abdominal septic shock-endotoxin adsorption treatment (ASSET)-endotoxin removal in abdominal and urogenital septic shock with the Alteco® LPS adsorber: study protocol for a double-blinded, randomized placebo-controlled trial. Trials. 2016; 17: 587.
 Turani F, Barchetta R, Falco M, Busatti S, Weltert L. Continuous renal replacement therapy with the adsorbing filter oXiris in septic patients: a case series. Blood Purification. 2019; 47: 1–5.
 Schwindenhammer V, Girardot T, Chaulier K, Grégoire A, Monard C, Huriaux L, et al. oXiris® use in septic shock: experience of two french centres. Blood Purification. 2019; 47: 1–7.
 Broman ME, Hansson F, Vincent JL, Bodelsson M. Endotoxin and cytokine reducing properties of the oXiris membrane in patients with septic shock: a randomized crossover double-blind study. PLoS One. 2019; 14: e0220444.
 Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Critical Care Medicine. 2021; 49: e1063–e1143.
 Spoelstra-de Man AME, Elbers PWG, Oudemans-Van Straaten HM. Vitamin C: should we supplement? Current Opinion in Critical Care. 2018; 24: 248–255.
 Shukla P, Rao GM, Pandey G, Sharma S, Mittapelly N, Shegokar R, et al. Therapeutic interventions in sepsis: current and anticipated pharmacological agents. British Journal of Pharmacology. 2014; 171: 5011–5031.
 Moskowitz A, Andersen LW, Huang DT, Berg KM, Grossestreuer AV, Marik PE, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Critical Care. 2018; 22: 283.
 Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017; 151: 1229–1238.
 Masood H, Burki AM, Sultan A, Sharif H, Ghauri A, Khan S, et al. Effect of intravenous vitamin C, thiamine, and hydrocortisone (the metabolic resuscitation protocol) on early weaning from vasopressors in patients with septic shock. a descriptive case series study. Cureus. 2019; 11: e5016.
 Mitchell AB, Ryan TE, Gillion AR, Wells LD, Muthiah MP. Vitamin C and thiamine for sepsis and septic shock. The American Journal of Medicine. 2020; 133: 635–638.
 Hwang SY, Park JE, Jo IJ, Kim S, Chung SP, Kong T, et al; Korean Shock Society (KoSS) Investigators. Combination therapy of vitamin C and thiamine for septic shock in a multicentre, double-blind, randomized, controlled study (ATESS): study protocol for a randomized controlled trial. Trials. 2019; 20: 420.
 Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al; VITAMINS Trial Investigators. Effect of vitamin C, hydrocortisone, and thiamine vs. hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020; 323: 423–431.
 Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, et al; LOVIT Investigators and the Canadian Critical Care Trials Group. Intravenous vitamin C in adults with sepsis in the intensive care unit. The New England Journal of Medicine. 2022; 386: 2387–2398.
 Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, et al; VICTAS Investigators. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA. 2021; 325: 742–750.
 Sriskandan S, Ferguson M, Elliot V, Faulkner L, Cohen J. Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. Journal of Antimicrobial Chemotherapy. 2006; 58: 117–124.
 Olas K, Butterweck H, Teschner W, Schwarz HP, Reipert B. Immunomodulatory properties of human serum immunoglobulin A: anti-inflammatory and pro-inflammatory activities in human monocytes and peripheral blood mononuclear cells. Clinical and Experimental Immunology. 2005; 140: 478-490.
 Schedel I, Dreikhausen U, Nentwig B, Höckenschnieder M, Rauthmann D, Balikcioglu S, et al. Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Critical Care Medicine. 1991; 19: 1104–1113.
 Wolf HM, Hauber I, Gulle H, Samstag A, Fischer MB, Ahmad RU, et al. Anti-inflammatory properties of human serum IgA: induction of IL-1 receptor antagonist and Fc alpha R (CD89)-mediated down-regulation of tumour necrosis factor-alpha (TNF-alpha) and IL-6 in human monocytes. Clinical and Experimental Immunology. 1996; 105: 537–543.
 Wolf HM, Fischer MB, Pühringer H, Samstag A, Vogel E, Eibl MM. Human serum IgA downregulates the release of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6) in human monocytes. Blood. 1994; 83: 1278–1288.
 Oesser S, Schulze C, Seifert J. Protective capacity of a IgM/IgA-enriched polyclonal immunoglobulin-G preparation in endotoxemia. Research in Experimental Medicine. 1999; 198: 325–339.
 Trautmann M, Held TK, Susa M, Karajan MA, Wulf A, Cross AS, et al. Bacterial lipopolysaccharide (LPS)-specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product. Clinical and Experimental Immunology. 1998; 111: 81–90.
 Norrby-Teglund A, Haque KN, Hammarström L. Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis. Journal of Internal Medicine. 2006; 260: 509–516.
 Busani S, Roat E, Serafini G, Mantovani E, Biagioni E, Girardis M. The role of adjunctive therapies in septic shock by gram negative MDR/XDR infections. Canadian Journal of Infectious Diseases and Medical Microbiology. 2017; 2017: 1–6.
 Reinhart K, Brunkhorst FM, Bone HG, Bardutzky J, Dempfle CE, Forst H, et al; German Sepsis Society; German Interdisciplinary Association of Intensive Care and Emergency Medicine. Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German sepsis society (deutsche sepsis-gesellschaft e.V. (DSG)) and the German interdisciplinary association of intensive care and emergency medicine (deutsche interdisziplinäre vereinigung für intensivund notfallmedizin (DIVI)). German Medical Science. 2010; 8: Doc14.
 Werdan K, Pilz G, Bujdoso O, Fraunberger P, Neeser G, Schmieder RE, et al; Score-Based Immunoglobulin Therapy of Sepsis (SBITS) Study Group. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Critical Care Medicine. 2007; 35: 2693–2701.
 Cavazzuti I, Serafini G, Busani S, Rinaldi L, Biagioni E, Buoncristiano M, et al. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Medicine. 2014; 40: 1888–1896.
 Rossmann FS, Kropec A, Laverde D, Saaverda FR, Wobser D, Huebner J. In vitro and in vivo activity of hyperimmune globulin preparations against multiresistant nosocomial pathogens. Infection. 2015; 43: 169–175.
 Cui J, Wei X, Lv H, Li Y, Li P, Chen Z, et al. The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis. Annals of Intensive Care. 2019; 9: 27.
 Sherman KE, Sjogren M, Creager RL, Damiano MA, Freeman S, Lewey S, et al. Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial. Hepatology. 1998; 27: 1128–1135.
 Chan HL, Tang JL, Tam W, Sung JJ. The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis. Alimentary Pharmacology & Therapeutics. 2001; 15: 1899–1905.
 Dominari A, Hathaway Iii D, Pandav K, Matos W, Biswas S, Reddy G, et al. Thymosin alpha 1: a comprehensive review of the literature. World Journal of Virology. 2020; 9: 67–78.
 Liu F, Wang HM, Wang T, Zhang YM, Zhu X. The efficacy of thymosin α1 as immunomodulatory treatment for sepsis: a systematic review of randomized controlled trials. BMC Infectious Diseases. 2016; 16: 488.
 Zhang Y, Chen H, Li YM, Zheng SS, Chen YG, Li LJ, et al. Thymosin alpha1- and ulinastatin-based immunomodulatory strategy for sepsis arising from intra-abdominal infection due to carbapenem-resistant bacteria. The Journal of Infectious Diseases. 2008; 198: 723–730.
 Han D, Shang W, Wang G, Sun L, Zhang Y, Wen H, et al. Ulinastatin-and thymosin α1-based immunomodulatory strategy for sepsis: a meta-analysis. International Immunopharmacology. 2015; 29: 377–382.
 Davies R, O’Dea K, Gordon A. Immune therapy in sepsis: are we ready to try again? Journal of the Intensive Care Society. 2018; 19: 326–344.
 Pant A, Mackraj I, Govender T. Advances in sepsis diagnosis and management: a paradigm shift towards nanotechnology. Journal of Biomedical Science. 2021; 28: 6.
 Flohé S, Lendemans S, Selbach C, Waydhas C, Ackermann M, Schade FU, et al. Effect of granulocyte-macrophage colony-stimulating factor on the immune response of circulating monocytes after severe trauma. Critical Care Medicine. 2003; 31: 2462–2469.
 Nierhaus A, Montag B, Timmler N, Frings DP, Gutensohn K, Jung R, et al. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Medicine. 2003; 29: 646–651.
 Flohé S, Börgermann J, Domínguez FE, Majetschak M, Lim L, Kreuzfelder E, et al. Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass, and severe sepsis. Shock. 1999; 12: 17–24.
 Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, et al. Granulocyte–macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression. American Journal of Respiratory and Critical Care Medicine. 2009; 180: 640–648.
 Piguet PF, Grau GE, de Kossodo S. Role of granulocyte-macrophage colony-stimulating factor in pulmonary fibrosis induced in mice by bleomycin. Experimental Lung Research. 1993; 19: 579–587.
 Serafini P, Carbley R, Noonan KA, Tan G, Bronte V, Borrello I. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Research. 2004; 64: 6337–6343.
 Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Medicine. 2011; 37: 525–532.
 Nelson LA. Use of granulocyte-macrophage colony-stimulating factor to reverse anergy in otherwise immunologically healthy children. Annals of Allergy, Asthma & Immunology. 2007; 98: 373–382.
 Pinder EM, Rostron AJ, Hellyer TP, Ruchaud-Sparagano MH, Scott J, Macfarlane JG, et al. Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis. Thorax. 2018; 73: 918–925.
 Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nature Reviews Nephrology. 2018; 14: 121–137.
 US National Library of Medicine. ClinicalTrials.gov. 2016. Available at: http://clinicaltrials.gov/ct2/show/NCT02361528 (Accessed: 08 September 2016).
 Sierro S, Romero P, Speiser DE. The CD4-like molecule LAG-3, biology and therapeutic applications. Expert Opinion on Therapeutic Targets. 2011; 15: 91–101.
 Döcke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nature Medicine. 1997; 3: 678–681.
 Grimaldi D, Pradier O, Hotchkiss RS, Vincent JL. Nivolumab plus interferon-γ in the treatment of intractable mucormycosis. The Lancet Infectious Diseases. 2017; 17: 18.
 Cutino-Moguel MT, Eades C, Rezvani K, Armstrong-James D. Immunotherapy for infectious diseases in haematological immunocompromise. British Journal of Haematology. 2017; 177: 348–356.
Vol., Issue , Invalid dateTable of contents
Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.
Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.
Chemical Abstracts Service Source Index The CAS Source Index (CASSI) Search Tool is an online resource that can quickly identify or confirm journal titles and abbreviations for publications indexed by CAS since 1907, including serial and non-serial scientific and technical publications.
Index Copernicus The Index Copernicus International (ICI) Journals database’s is an international indexation database of scientific journals. It covered international scientific journals which divided into general information, contents of individual issues, detailed bibliography (references) sections for every publication, as well as full texts of publications in the form of attached files (optional). For now, there are more than 58,000 scientific journals registered at ICI.
Geneva Foundation for Medical Education and Research The Geneva Foundation for Medical Education and Research (GFMER) is a non-profit organization established in 2002 and it works in close collaboration with the World Health Organization (WHO). The overall objectives of the Foundation are to promote and develop health education and research programs.
Scopus: CiteScore 0.5(2021) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.
Embase Embase (often styled EMBASE for Excerpta Medica dataBASE), produced by Elsevier, is a biomedical and pharmacological database of published literature designed to support information managers and pharmacovigilance in complying with the regulatory requirements of a licensed drug.